Amphiphilic lipid-peptide engineered placenta-derived mesenchymal stem cells for liver fibrosis treatment.

Human mesenchymal stem cells (hMSCs) hold significant promise in regenerative medicine due to their ability to reduce inflammation and promote tissue repair. However, their therapeutic potential is often compromised by their high susceptibility to apoptosis under oxidative stress, prevalent in the microenvironment of the target tissues. Our previous study showed that fucoxanthin, a carotenoid derived from brown algae, can improve the viability of placenta-derived mesenchymal stem cells (PL-MSCs) by reducing intracellular ROS levels through the activation of the PI3K/Akt/Nrf-2 signaling pathway. In this study, we further investigate the mechanisms underlying the protective effect of fucoxanthin against oxidative stress-induced apoptosis in PL-MSCs, using an in vitro model. PL-MSCs were cultured with 750 µM H2O2 to induce oxidative stress and treated with various concentrations of fucoxanthin for 48 h. The effect of fucoxanthin on PL-MSC apoptosis under oxidative stress conditions was determined using CCK-8, Annexin V/DRAQ7™ apoptosis assays, as well as the expression of apoptosis-related genes and proteins. The effect of fucoxanthin on the transcriptome of PL-MSCs under oxidative stress conditions was also assessed by high-throughput Nanostring analysis. The results showed that fucoxanthin significantly decreased the apoptosis of PL-MSCs under oxidative stress in a dose-dependent manner by reducing the expression of pro-apoptotic proteins and inhibiting their activation, while increasing the expression of anti-apoptotic proteins in these cells. Furthermore, fucoxanthin also downregulates the expression of genes associated with the endoplasmic reticulum stress, p53-induced apoptosis, while increasing the expression of genes involved in the regulation of the cell cycle, DNA damage repair, cytokine signaling, nucleotide synthesis, PI3K/mTOR pathway and AMPK pathway in PL-MSCs under oxidative stress conditions. Taken together, the findings provide compelling evidence that fucoxanthin protects PL-MSCs against oxidative stress-induced apoptosis by modulating the expression of various genes involved in DNA damage repair, ER stress response, p53-induced apoptosis in these cells. This suggests that fucoxanthin could be used in combination with other agents to increase the therapeutic potential of MSCs by improving their viability under conditions of oxidative stress in the target tissue microenvironment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13287-025-04629-3.

Neovasculogenesis induced by stem cell therapy is an innovative approach to improve critical limb ischemia (CLI) in diabetes. Mesenchymal stem cells (MSCs) are ideal candidates due to their angiogenic and immunomodulatory features. The aim of this study is to determine the therapeutic effects of human placenta-derived MSCs (P-MSCs) on diabetic CLI, with or without exogenous insulin administration, and the underlying mechanism of any effect. A series of in vitro experiments were performed to assess the stemness and vasculogenic activity of P-MSCs. P-MSCs were intramuscularly injected at two different doses with and without the administration of insulin. The efficacy of P-MSC transplantation was evaluated by ischemia damage score, ambulatory score, laser Doppler perfusion image (LDPI), capillary, and vascular density. In vivo imaging was applied to track the implanted P-MSCs. In vivo differentiation and in situ secretion of angiogenic cytokines were determined. In vitro experimental outcomes showed the differentiation potential and potent paracrine effect of P-MSCs. P-MSCs survived in vivo for at least 3 weeks and led to the acceleration of ischemia recovery, due to newly formed capillaries, increased arterioles, and secretion of various proangiogenic factors. P-MSCs participate in angiogenesis and vascularization directly through differentiation and cytokine expression.

Mesenchymal stem cells (MSCs) being injected into the body can stimulate or decelerate carcinogenesis. Here, the direction of influence of human placenta-derived MSCs (P-MSCs) on the Lewis lung carcinoma (LLC) tumor development and metastatic potential is investigated in C57BL/6 mice depending on the injection method. After intramuscular co-inoculation of LLC and P-MSCs (LLC + P-MSCs), the growth of primary tumor and angiogenesis are slowed down compared to the control LLC on the 15th day. This is explained by the fact of a decrease in the secretion of proangiogenic factors during in vitro co-cultivation of an equal amount of LLC and P-MSCs. When P-MSCs are intravenously (i.v.) injected in the mice with developing LLC (LLC + P-MSCs(i.v.)), the tumor growth and angiogenesis are stimulated on the 15th day. A highly activated secretion of proangiogenic factors by P-MSCs in a similar in vitro model can explain this. In both the models compared to the control on the 23rd day, there is no significant difference in the tumor growth, while angiogenesis remains correspondingly decelerated or stimulated. However, in both the models, the total volume and number of lung metastases constantly increase compared to the control: it is mainly due to small-size metastases for LLC + P-MSCs(i.v.) and larger ones for LLC + P-MSCs. The increase in the rate of LLC cell dissemination after the injection of P-MSCs is explained by the disordered polyploidy and chromosomal instability, leading to an increase in migration and invasion of cancer cells. After LLC + P-MSCs co-inoculation, the tumor cell karyotype has the most complex and heterogeneous chromosomal structure. These findings indicate a bidirectional effect of P-MSCs on the growth of LLC in the early periods after injection, depending on the injection method, and, correspondingly, the number of contacting cells. However, regardless of the injection method, P-MSCs are shown to increase LLC aggressiveness related to cancer-associated angiogenesis and metastasis activation in the long term.

BackgroundMesenchymal stem cells (MSCs) have a great potential ability for endothelial differentiation, contributing to an effective means of therapeutic angiogenesis. Placenta-derived mesenchymal stem cells (PMSCs) have gradually attracted attention, while the endothelial differentiation has not been fully evaluated in PMSCs. Metabolism homeostasis plays an important role in stem cell differentiation, but less is known about the glycometabolic reprogramming during the PMSCs endothelial differentiation. Hence, it is critical to investigate the potential role of glycometabolism reprogramming in mediating PMSCs endothelial differentiation.MethodsDil-Ac-LDL uptake assay, flow cytometry, and immunofluorescence were all to verify the endothelial differentiation in PMSCs. Seahorse XF Extracellular Flux Analyzers, Mito-tracker red staining, Mitochondrial membrane potential (MMP), lactate secretion assay, and transcriptome approach were to assess the variation of mitochondrial respiration and glycolysis during the PMSCs endothelial differentiation. Glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) was considered a potential modulator for endothelial differentiation in PMSCs by small interfering RNA. Furthermore, transwell, in vitro Matrigel tube formation, and in vivo Matrigel plug assays were performed to evaluate the effect of PFKFB3-induced glycolysis on angiogenic capacities in this process.ResultsPMSCs possessed the superior potential of endothelial differentiation, in which the glycometabolic preference for glycolysis was confirmed. Moreover, PFKFB3-induced glycometabolism reprogramming could modulate the endothelial differentiation and angiogenic abilities of PMSCs.ConclusionsOur results revealed that PFKFB3-mediated glycolysis is important for endothelial differentiation and angiogenesis in PMSCs. Our understanding of cellular glycometabolism and its regulatory effects on endothelial differentiation may propose and improve PMSCs as a putative strategy for clinical therapeutic angiogenesis.

Manufacture and preparation of human placenta-derived mesenchymal stromal cells for local tissue delivery

The well-developed placentation is fundamental for the reproductive pregnancy while the defective placental development is the pathogenetic basis of preeclampsia (PE), a dangerous complication of pregnancy comprising the leading causes of maternal and perinatal morbidity and mortality. Placenta-derived mesenchymal stem cells (PMSCs) are a group of multipotent stem cells that own a potent capacity of differentiating into constitutive cells of vessel walls. Additionally, with the paracrine secretion of various factors, PMSCs inextricably link and interact with other component cells in the placenta, collectively improving the placental vasculature, uterine spiral artery remolding, and uteroplacental interface immunoregulation. Recent studies have further indicated that preeclamptic PMSCs, closely implicated in the abnormal crosstalk between other ambient cells, disturb the homeostasis and development in the placenta. Nevertheless, PMSCs transplantation or PMSCs exosome therapies tend to improve the placental vascular network and trophoblastic functions in the PE model, suggesting PMSCs may be a novel and putative therapeutic strategy for PE. Herein, we provide an overview of the multifaceted contributions of PMSCs in early placental development. Thereinto, the intensive interactions between PMSCs and other component cells in the placenta were particularly highlighted and further extended to the implications in the pathogenesis and therapeutic strategies of PE.

Angiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 105) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P < 0.05). In addition, histological analysis showed more mature follicles and less atresia and restoration of expanded blood vessels in the ovaries of the OVX PD-MSC Tx group than those of the NTx group (*P < 0.05). Furthermore, folliculogenesis-related gene expression was also significantly increased in the PD-MSC Tx group (*P < 0.05). Vascular endothelial growth factor (VEGF) and VEGF receptor 2 expressions were increased in the ovaries of the OVX PD-MSC Tx group compared to the NTx group through PI3K/AKT/mTOR and GSK3β/β-catenin pathway activation. Interestingly, ex vivo cocultivation of damaged ovaries and PD-MSCs or treatment with recombinant VEGF (50 ng/ml) increased folliculogenic factors and VEGF signaling pathways. Notably, compared to recombinant VEGF, PD-MSCs significantly increased folliculogenesis and angiogenesis (*P < 0.05). These findings suggest that VEGF secreted by PD-MSCs promotes follicular development and ovarian function after OVX through vascular remodeling. Therefore, these results provide fundamental data for understanding the therapeutic effects and mechanism of stem cell therapy based on PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.Vascular endothelial growth factor secreted by placenta-derived mesenchymal stem cells (PD-MSCs) promotes follicular development and ovarian function after ovariectomy through vascular remodeling. These results provide fundamental data for understanding the therapeutic mechanisms of stem cell therapy based on placenta-derived mesenchymal stem cells PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.

The immunomodulatory effects of mesenchymal stem cells (MSCs) are an important mediator of their therapeutic effects in stem cell therapy and regenerative medicine. The regulation mechanism of MSCs is orchestrated by several factors in both intrinsic and extrinsic events. Recent studies have shown that the dynamic expression of cytokines secreted from MSCs control T cell function and maturation by regulating the expression of FoxP3, which figures prominently in T cell differentiation. However, there is no evidence that placenta-derived mesenchymal stem cells (PD-MSCs) have strong immunomodulatory effects on T cell function and maturation via FoxP3 expression. Therefore, we compared the expression of FoxP3 in activated T cells isolated from peripheral blood and co-cultured with PD-MSCs or bone marrow-derived mesenchymal stem cells (BM-MSCs) and analyzed their effect on T cell proliferation and cytokine profiles. Additionally, we verified the immunomodulatory function of PD-MSCs by siRNA-mediated silencing of FoxP3. MSCs, including PD-MSCs and BM-MSCs, promoted differentiation of naive peripheral blood T cells into CD4+CD25+FoxP3+ regulatory T (Treg) cells. Intriguingly, the population of CD4+CD25+FoxP3+ Treg cells co-cultured with PD-MSCs was significantly expanded in comparison to those co-cultured with BM-MSCs or WI38 cells (p<0.05, p<0.001). Dynamic expression patterns of several cytokines, including anti- and pro-inflammatory cytokines and members of the transforming growth factor-beta (TGF-β) family secreted from PD-MSCs according to FoxP3 expression were observed. The results suggest that PD-MSCs have an immunomodulatory effect on T cells by regulating FoxP3 expression.

Human placenta-derived mesenchymal stem cells (P-MSCs) have drawn increasing attention in the field of stem cell research due to their potential in clinical applications as well as their rich and easy to procure cell source. While studies demonstrating the potential of P-MSCs for therapeutic transplantations have been documented, a clinically compliant procedure for P-MSC expansion in vitro has yet to be established. To this end, previous studies have demonstrated that MSCs of bone marrow and cord blood origins cultured in human cord blood serum (hCBS) are comparable to those cultured in fetal bovine serum (FBS), indicating that hCBS may be an alternative to FBS for the development of in vitro cell expansion procedures free of animal components. However, stem cells from origins other than bone marrow or cord blood, particularly from human placental tissues, which have demonstrated a good potential for clinical applications, have not been characterized under similar conditions. In this study, in an attempt to define a clinically compliant protocol for P-MSC expansion in vitro, we examined the effects of human hCBS as a replacement for FBS on cell proliferation capacity, differentiation potential, MSC-specific phenotypic expression and the genetic stability of P-MSCs in cultures. P-MSCs expanded in vitro in autologous hCBS maintained the capacity of self‑renewal and expressed surface antigens characteristic of bone marrow-derived mesenchymal stem cells. Under differentiation conditions, the P-MSCs expanded in hCBS developed into adipogenic, osteogenic and neurogenic cell phenotypes. Chromosomal karyotyping and single cell gel electrophoresis analysis demonstrated that P-MSCs cultured in autologous hCBS were genetically stable. These results suggest that autologous hCBS may be used as an alternative to FBS for the in vitro expansion of P-MSCs for clinical applications.

Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta-derived mesenchymal stem cells were induced to differentiate into neural stem cells, which were then transplanted into the spinal cord after local spinal cord injury in rats. The motor functional recovery and pathological changes in the injured spinal cord were observed for 3 successive weeks. The results showed that human placenta-derived mesenchymal stem cells can differentiate into neuron-like cells and that induced neural stem cells contribute to the restoration of injured spinal cord without causing transplant rejection. Thus, these cells promote the recovery of motor and sensory functions in a rat model of spinal cord injury. Therefore, human placenta-derived mesenchymal stem cells may be useful as seed cells during the repair of spinal cord injury.

To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1β) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

Introduction Regenerative medicine has become a light at the end of the tunnel for countless patients who have suffered from diseases previously considered incurable. Stem cell therapy is central to this revolutionary progress and has already made huge advances in recent years. Stem cells have the potential to regenerate tissues, repair organs, and even modulate immune responses, making them a key to delivering innovative treatments for a broad spectrum of medical conditions. This editorial describes recent progress in stem cell therapy as well as its promise as a regenerative medicine[1]. Stem Cells have unique Properties. Stem cells have unique properties that make them of great value in therapeutic applications. This allows them to self-renew and differentiate into specialized cell types with immense possibilities of being used in treating degenerative diseases, tissue injuries, and even genetic disorders. Each type is classified broadly into embryonic stem cells (ESCs), adult stem cells (ASCs), and induced pluripotent stem cells (iPSCs) with particular advantages. For example, ESCs are pluripotent and can differentiate into almost any cell type, while the more accessible and less ethically controversial MSCs like the ASCs[2]. Pioneered most recently by Shinya Yamanaka, recent breakthroughs in iPSC technology have further revolutionized the field. IpsCs overcome many of the limitations of ESCs by reprogramming somatic cells into a pluripotent state. It has accelerated the development of patient-specific therapies – personalized regenerative solutions[3]. Stem Cell Therapy Success Stories Stem cell therapies have already had tremendous success in treating multiple different medical conditions. Therapies have also been shown to be effective in treating Parkinson’s disease, spinal cord injuries, and stroke in neurological disorders. Damaged neurons have been replaced with transplanted stem cells and lost functions have been restored[4]. While recent clinical trials using MSCs and iPSCs for stroke recovery have revealed improved motor function as well as reduced inflammation, they represent a great leap forward in this field. Repairing damaged heart tissue that results from myocardial infarction has been explored using cardiomyocyte transplantation from ESCs and iPSCs. In preclinical and clinical studies, these therapies not only support tissue regeneration but also enhance cardiac function and survival outcomes[5]. The differentiation of ESCs and iPSCs into insulin-secreting β cells for use in the treatment of type- 1 diabetes represents another major milestone in stem cell therapy. But β cells transplanted into the bloodstream can regulate blood glucose levels, and at last, this represents a realistic prospect of a cure[6, 7]. Unfortunately, hematopoietic stem cell transplantation (HSCT) remains the gold standard for treating blood-related disorders, such as leukemia, aplastic anemia, and immune deficiencies. HSCT has been further made safer and more effective by advances in gene editing technologies such as CRISPR-Cas9, which now allow for targeted genetic therapies. MSCs are being widely investigated in the orthopedic field for their potential to regenerate cartilage, bone, and muscle tissue. Stem cell therapy has shown a lot of promise in osteoarthritis, fractures, and tendon injuries, where the therapies help to speed up healing and reduce pain[8]. Challenges of Stem Cell Therapy Sure, the promise of stem cell therapy is undeniable, but a host of challenges must be overcome first to make it a mainstream clinical tool. Despite all of this, safety concerns remain paramount: tumorigenesis, immune rejection, and unintended differentiation. Equally important is standardization and regulation, which will help develop consistent protocols for stem cell isolation, culture, and transplantation with reproducible outcomes from clinical trials. In addition, stem cell therapies are very expensive, which limits access, especially in low and middle-income countries. However, ESCs have continued to raise ethical concerns, particularly in the area of ESCs, and therefore alternative sources such as iPSCs and adult stem cells are needed[9]. Future Directions Overcoming these challenges is a future challenge for bioengineering, nanotechnology, and gene editing. For example, 3D bio-printed tissues and organoids bring together stem cell technology and tissue engineering to provide functional tissues for transplantation. These innovations could change the way we deal with organ failure and more advanced medical conditions[10]. Conclusion Stem cell therapy enters into a new era of progressive continuous progress. With the continued expansion of clinical trials and increasing technology, stem cell therapies have the potential to transform the treatment landscape for many diseases and injuries. Still, there is plenty of work to be done, but the convergence of interdisciplinary innovations presents a strong foundation for hope. With the participation of scientists, clinicians, policymakers, and industry stakeholders, stem cell research can be translated into safe, effective, and accessible therapies benefiting millions of patients with the possibility to recover and improve their quality of life. Regenerative medicine has a promising future and stem cells are at the center of that progress. Through innovation and addressing current challenges, we can unleash the full power of stem cell therapies to provide transformative solutions to patients around the world.

The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

Diabetic foot has become the main cause of non-traumatic amputation. Stem cell therapy, especially mesenchymal stem cells (MSCs), holds a great promise as a therapy for diabetic foot with ischemia limb arterial disease. The aim of this pilot study is to evaluate the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment for diabetic patients with critical limb ischemia (CLI). Four eligible diabetic patients with CLI were consecutively enrolled in this pilot study. On the base of the standard-of-care treatment, these patients accepted P-MSCs treatment by intramuscular injection for successive 3 times at an interval of 4 weeks, and the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment were evaluated. There were no serious adverse events during the period of P-MSCs injection and the 24-weeks follow-up period. The clinical ischemic features of patients were improved 24 weeks after P-MSCs treatment. The scores of resting pain and limb coldness significantly decreased, and pain-free walking distance significantly increased from baseline to 24 weeks after P-MSCs therapy. The resting ankle brachial index increased, but no statistically significant difference was found. The findings of magnetic resonance angiography showed the increase of collateral vessel formation in one patient, but there were no significant changes observed in the other patients. The data in this pilot study indicated that multiple intramuscular P-MSCs injections may be a safe and effective alternative therapy for diabetic patients with CLI, and larger, placebo-controlled, perspective studies are needed to prove these results.

Placenta-derived mesenchymal stem cells (PD-MSCs) were highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs)were found to mediate one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with migrated naïve PD-MSCs, migrated PRL-1(+) PD-MSCs showed improved integrin-dependent migration abilitythrough Ras homolog (RHO) family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplantedPRL-1(+) PD-MSCs through the integrin family. Additionally, an increase inplatelet-derived growth factor receptor A (PDGFRA) by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSC transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs byactivating the interleukin-6 (IL-6) signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understandingof therapeutic mechanisms based on miRNA-mediated stem-cell therapy in liver diseases.